Supplemental Readings and References
molecule. The TCA cycle is amphibolic; i.e., it serves
as a catabolic and an anabolic pathway.
that utilize intermediates of the cycle as precursors
for the biosynthesis of other molecules are listed be-
low. Some of these reactions occur outside the mito-
1. Citrate + ATP + CoA
+ oxaloacetate + ADP + P,. This reaction takes
place in the cytoplasm and is a source of acetyl-CoA
for fatty acid biosynthesis.
2. a-Ketoglutarate + alanine — glutamate + pyruvate.
3. a-Ketoglutarate ->• succinate + CO
. This reaction
is involved in the hydroxylation of prolyl and lysyl
residues of protocollagen, a step in the synthesis of
4. Succinyl-CoA + glycine —>■
(5-aminolevulnic acid
(ALA). ALA is then utilized for the synthesis of
5. Succinyl-CoA + acetoacetate
acetoacetyl-CoA +
succinate. This reaction is important in the activation
of acetoacetate (a ketone body) and hence for its
utilization in extrahepatic tissues.
. Oxaloacetate + alanine ^ aspartate + pyruvate.
7. Oxaloacetate + GTP
— y
phosphoenolpyruvate +
GDP + C 02.
Utilization of intermediates in these reactions leads to
their depletion and hence to a slowdown of the cycle un-
less they are replenished by the replacement or anaplerotic
reactions listed below:
biotin, Mg2+
1. Pyruvate + CO
+ A T P----------
oxaloacetate +
ADP + P;. This reaction, catalyzed by pyruvate
carboxylase, is the most important anaplerotic
reaction in animal tissues and occurs in mitochondria.
Pyruvate carboxylase is an allosteric enzyme that
requires acetyl-CoA for activity (see gluconeogenesis;
Chapter 15).
2. Pyruvate + CO
+ NADPH + H+ ^ L-malate +
3. Oxaloacetate and a-ketoglutarate may also be
obtained from aspartate and glutamate, respectively,
by transaminase reactions.
4. Oxaloacetate obtained in the reverse of reaction (7),
Regulation o f the TCA Cycle
TCA cycle substrates oxaloacetate and acetyl-CoA and
the product NADH are the critical regulators. The avail-
ability of acetyl-CoA is regulated by pyruvate dehydroge-
nase complex. The TCA cycle enzymes citrate synthase,
isocitrate dehydrogenase and the a-ketoglutarate de-
hydrogenase complex are under regulation by many
metabolites (discussed above) to maintain optimal cellu-
lar energy needs. Overall fuel homeostasis is discussed in
Chapter 22.
Energetics o f the TCA Cycle
Oxidation of one molecule of acetyl-CoA in the cycle
yields three NADH, one FADH2, and one GTP. Trans-
port of reducing equivalents in the electron transport chain
from one NADH molecule yields three ATP and from
, two ATP (see Chapter 14). Thus, oxidation of
one molecule of acetyl-CoA yields 12 ATP. Since one glu-
cose molecule yields two acetyl-CoA, the yield of ATP is
24. In addition, in the oxidation of glucose to acetyl-CoA,
two other steps yield four NADH (i.e., glyceraldehyde-
3-phosphate dehydrogenase and pyruvate dehydrogenase
reactions), since one glucose molecule yields two triose
phosphate molecules, which accounts for 12 more ATP.
Oxidation of one molecule of glucose to two of pyru-
vate yields two ATP (see under glycolysis) by substrate-
level phosphorylation. Thus, complete oxidation of one
molecule of glucose can yield 38 ATP. In cells depen-
dent only on anaerobic glycolysis, glucose consumption
has to be considerably greater to derive an amount of en-
ergy equal to that obtainable from aerobic oxidation (two
ATP versus 38 ATP per glucose). However, in cells ca-
pable of both aerobic and anaerobic metabolism, glycol-
ysis, the TCA cycle, and oxidation in the electron trans-
port chain are integrated and regulated so that only just
enough substrate is oxidized to satisfy the energy needs
of a particular cell. In the presence of oxygen, a reduction
in glucose utilization and lactate production takes place, a
phenomenon known as the
Pasteur effect.
The depression
of rate of flux through glycolysis can be explained in part
by the accumulation of allosteric inhibitors (e.g., ATP)
-phosphofructokinase and pyruvate kinase, together
with the supply of cofactors and coenzymes of certain
key enzymes (e.g., glyceraldehyde-3-phosphate dehydro-
Supplemental Readings and References
D. C. De Vivo, R. R. Trifiletti, R. I. Jacobson, et at: Defective glucose
transport across the blood-brain barrier as a cause of persistent hypogly-
corrhachia, seizures and developmental delay.
N ew E n g la n d J o u rn a l o f
M ed icin e
3 2 5 ,703 (1991).
O. N. Elpeleg, W. Ruitenbeek, C. Jakobs, et at: Congenital lacticacidemia
caused by lipoamide dehydrogenase deficiency with favorable outcome.
J o u rn a l o f P ed ia trics
126, 72 (1995).
R. A. Fishman: The glucose-transporter protein and glucopenic brain injury.
N ew E n g la n d J o u rn a l o f M ed ic in e
325, 731 (1991).
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